Diseases that threaten mental health have been linked to the genetic make-up of an individual. Studies of families or groups of patients have sought to determine the specific genes that may influence the course of disease. Only few genetic variants can be directly linked to disease, but many gene variants have been shown to lend a susceptibility to disease.[unreadable] [unreadable] Animal modeling is sometimes the only method that can be used to sort out the function of genes that have been identified in patient studies and to test the hypothesis that suspect genes might effect behavior or development of the nervous system. Animals in which genes have been manipulated are very useful for studing these effects. Mouse and rat models are produced by the NIMH transgenic core facility for this reason.[unreadable] [unreadable] Production of transgenic mice[unreadable] The NIMH transgenic core uses most of its resources to create transgenic animals and provide other transgenic animal services to neuroscientists at NIH. This allows NIH scientists to test models of disease, investigate the role of specific genes in behavior and the development of the nervous system. Scientists at NIH can quickly apply basic research directly to an intact organism. Over the last year (FY2008; October 2007 through September 2008) the core facility has worked on more than 53 different transgenic projects. By using these techniques the core generates mice with an altered genomes genes are either added, deleted or altered. In addition to the transgenic mice that were produced, the core facility archived 36 different mouse lines by cryopreservation. Thirty-three different transgenic lines were rederived (mice from these lines were used to produce embryos that could be transferred into the specific pathogen-free animal facility).[unreadable] All of these projects are undertaken as a service and will be described in the reports from individual investigators. But they can be categorized into general areas: [unreadable] 1) many projects exploit the use of general mechanism to induce or alter the expression of another transgene. The cre recombinase was used to effect genetic changes in specific temporal and spatial compartments. Several investigators have used systems that are induced by an exogenous agent (tetracycline or tamoxifen). [unreadable] 2) The GENSAT project uses this approach. The core has archived and distributed several GENSAT lines that have been evaluated and found to be useful for neuroscience research.[unreadable] 3) In addition to these efforts to extend the utility of transgenic techniques there are many projects in which genes are disrupted or expressed in aberrant patterns to gauge the effect on behavior. Genes that have been implicated in schizophrenia and bipolar disorder and other innate behaviors have been targeted in this way for NIMH investigators.[unreadable] 4) Many projects have altered expression of molecules that have poorly defined function but are expressed in the nervous system in patterns that suggest a role in learning, memory or development.[unreadable] 5) And finally several projects have used inducible or specifically expressed toxins to ablate neural cells to see what roles these specific cells play in the function of the brain.[unreadable] [unreadable] Creation of animal models of human disease: [unreadable] Human disease models for two neurological disorders were developed by the core facility in 2007. That work has continued so that those mice have now been used in studies that have been published. The mice have been shared with many other laboratories. A third disorder is now being targeted.[unreadable] [unreadable] -Mucolipidosis IV is a disorder caused by any of several genetic alterations in the MCOLN1 gene. Patients have developmental delay, corneal clouding, retinal degeneration, hypergastrinemia, achlorohydria as well as some poorly defined brain anomalies. On the cellular level inclusion bodies are found in many tissues. The MCOLN1 protein appears to form a channel that is critical for the function of lysosomes. The mouse model of this ddisease was created by targeting the Mcoln1 gene in ES (embryonic stem) cells. In the past year we have targeted two other members of this gene family MCOLN2 and MCOLN3. These genes may have an even greater role in the development of the nervous system and may be useful replacements for Mcoln1 in patients.[unreadable] [unreadable] -Familial dysautonomia effects sensory and autonomic nerves and causes a range in severity of symptoms from temperature regulation to control of stomach reflux. The mouse model is made more complex since the complete disruption of the gene causes embryonic death. The strategy has been to replace the mouse gene with human transgenes of either the normal or disease-causing allele. This year, disease model mice have been treated with a drug to test its potential as a therapy in patients. [unreadable] [unreadable] -This year a model of q22 syndrome is being developed. Patients that inherit two disrupted copies of chromosome 22 fail to complete development of the nervous system. Several genes are located in this part of the chromosome, but Shank3 is the one most likely to be linked to disease. The SHANK3 protein may be critical in this disease because it is located near the synapse that is formed between two neurons. Questions about the connection of neurons during development may be answered with a mouse model for q22 syndrome.[unreadable] [unreadable] These models of genetic disease are being developed in the core facility and will be analyzed by laboratories that specialize in each of the aspects of the disease phenotype that is mimicked in the mouse model.[unreadable] [unreadable] Technology development[unreadable] -Derivation of embryonic stem cell lines: [unreadable] The core facility continues to develop new ES cell lines. Lines from the reference strain C57BL/6 have been developed. These are marked by ubiquitous expression of the green fluorescent protein (GFP). Now we are making ES cell lines that have the same genetic background, but carry a genetic allele for albinism. This will allow us to use a reference strain, but distinguish pups which carry the ES cells transgene by their coat color.[unreadable] -Transgenic rats[unreadable] For some behavior experiments rats provide a more useful result than mice. In order to take advantage of this difference we have begun generating transgenic rats. [unreadable] -Other projects to increase efficiency of transgenic production.[unreadable] We have begun studies to test the usefulness of using cultured sperm progenitors to carry transgenes. These cells can be cultured and the transgene introduced into the cells. Those cells may be manipulated before being introduced into the mouse"s testis. Other methods of introducing DNA into embryos of various ages are also being compared. Lentiviral vectors and new methods of electroporation will be compared.[unreadable] [unreadable] Additional publications that describe mice generated by the NIMH transgenic core:[unreadable] [unreadable] Usdin T, Paciaga M, Riordan T, Kuo J, Parmelee A, Peukova G, Caerini-Otero RD, Mezey E (2008) Tuberoinfundibular peptide of 39 residues is required for germ cell development. Endocrinology 149(9):4292.[unreadable] [unreadable] FegleyDB, Holmes A, Riordan T, Faber CA, Weiss JR, Ma S, Batkai S, Pacher P, Dobolyi A, Murphy A, Sleeman MW, Usdin T (2008) Increased fear and stress-related anxiety-like behaviour in mice lacking TIP39. Genes Brain Behav. (online prepublication 12 Aug 2008)